Insulin can get a bum rap. Although a mainstay of diabetes treatment, when secretion increases in response to a low-fat, high-carbohydrate
diet or insulin resistance, insulin has been purported to raise blood pressure, potentiate cardiovascular risk, and, to make
matters worse, promote weight gain (1,2). But many in the lay public, popular media, and health care are not aware (or choose not to acknowledge) that insulin predated
leptin as an adipostat hormone—one that circulates in the blood in proportion to body weight and binds to key brain centers
to lower body weight (3). However, to rehabilitate insulin’s reputation and validate its beneficial role in weight regulation requires strong evidence
because “obesity” and “insulin” are so frequently entwined.

Until recently, the mechanistic role of insulin in the central nervous system control of body weight had been worked out exclusively
in animal models (4–8), whereas evidence for its effect in humans remained circumstantial and controversial. For example, an inverse association
of postprandial insulin secretion at breakfast and a reduction in subsequent food intake at lunch has been reported in humans
(9) and is consistent with insulin’s role as an anorectic hormone. In contrast, intensive diabetes therapy that includes increasing
insulin dosage is frequently accompanied by unwanted weight gain and even obesity (10). Hence the conundrum: is insulin good or bad for body weight in humans? To answer the question of how central insulin action
regulates energy balance, insulin would need to be administered directly to brain centers involved in determining …